The Food Quality Protection Act (FQPA) of 1996 and several regulations
and executive orders have demanded that information concerning the
special susceptibility of infants and children be included when
assessing risk, setting tolerances, or registering chemicals for
use in the environment1. The inclusion
of this type of information is hampered by several difficulties,
including the assessment of exposure, the long latency of many diseases
influenced by the environment, the number of confounding exposures,
and the extrapolation of animal models to critical stages of human
development.

Biologic markers (biomarkers) can act as quantitative measures
of chemical exposures and biologically effective doses, as well
as early warning signals of biologic effect. Biomarkers may
help to characterize inter-individual susceptibilities, as well
as define critical windows of exposure. To be useful, biomarkers
need to be evaluated in terms of their specificity and sensitivity.
Biomarkers may be useful across all disciplines including asthma
and respiratory problems, developmental neurotoxicity, childhood
cancer, and endocrine disruption. Biomarkers have not been
developed nor used widely in children's environmental health.
Advances in this field may have important implications for the detection,
prevention, and treatment of environmentally induced diseases in
children.

The choice of biomarkers as a topic for a Request for Applications
(RFA) supporting FQPA is related to the requirements of the Act.
FQPA requires that aggregate exposure via multiple pathways and
cumulative risk from multiple chemicals be considered in assessing
risk to children2. Since biomarkers
often represent aggregate exposures and/or cumulative effects, they
offer potentially useful tools for conducting these kinds of assessments.
Because of this potential, the EPA's Science to Achieve Results
(STAR) Program is sponsoring research to develop and evaluate biomarkers
for use in assessing the risks posed by exposures to pesticides
among children. Although all classes of pesticides will be
considered, the organophosphates, triazine herbicides, and pyrethroids
are of particular interest to the STAR Program.

Background

Developing individuals (embryos, fetuses, newborns, infants, children,
and adolescents) are uniquely susceptible populations to insults
from environmental hazards3. Their
increased susceptibility can arise from increased exposure to environmental
toxins, increased exposure of individual organ systems, differences
in distribution of toxins, immaturity of metabolic pathways, immaturity
of excretory pathways, alterations in target organ susceptibility,
and a longer life span in which to express illness. Although
the enhanced susceptibility of infants and children to environmental
toxins has been shown in multiple studies, the nature and extent
of pediatric illness resulting from environmental exposure have
not been well characterized.

There are several reasons for this deficiency. First, documentation
of exposure is difficult in the fetal and pediatric population.
Pregnant women and children do not wear personal monitoring devices
such as those worn by workers in an occupational exposure setting.
Modeling of exposure is also difficult. There are few studies
documenting where children spend their time. Even in situations
with known exposures, the individual dose to a child is difficult
to document. The long latency of many environmentally induced
diseases makes their etiology difficult to determine. Thus,
retrospective studies are difficult to conduct. An individual
is also exposed to more than one environmental toxicant and probably
to other agents, which may confound the association of one toxicant
to an illness. Extrapolation from animal models to human children
is also difficult. Many of the critical stages of development
are not well characterized in animals. For example, an exposure
that occurs during puberty in children may be difficult to model
in an animal. Finally, classic epidemiology has limitations
in sensitivity. If thalidomide had caused only mental retardation
and not other effects, the rarity of the exposure would never have
significantly increased the normal rate of mental retardation above
background rates, and hence, thalidomide would not have been recognized
as a teratogen4. Biomarkers have
the potential to overcome many of these difficulties. They
may be used to identify the early stages of health impairment and
to understand basic mechanisms of exposure and response in research
and medical practice.

What Are Biomarkers?

Biomarkers are observable properties of an organism that can be
used in four general ways: (1) to identify the presence of an organism,
as in microbiology or forensic pathology, (2) to estimate the organism's
prior exposure, as in risk assessment, (3) to identify changes or
effects occurring in the organism, as in toxicology or diagnostic
medicine, and (4) to assess the underlying susceptibility of an
organism, as in genetics and pharmacology. For this solicitation,
three specific types of biomarkers will be considered:

 Biomarkers of exposure - exogenous chemicals, metabolite(s)
or the products of interactions between a pesticide and target molecules
or cells that are measured in a compartment within an organism.
This includes internal dosimeters of pesticide or metabolite concentrations
and markers of biologically effective doses.

 Biomarkers of effects - measurable alterations of an organism
that, depending on magnitude, can indicate a potential or established
health impairment or disease.

 Biomarkers of susceptibility - indicators of inherent or acquired
properties of an organism that may lead to an increase in the
internal dose of a pesticide or an increased level of the response
resulting from exposure to a specific pesticide.

Specific Research Areas
of Interest

The STAR Program is interested in supporting research to identify
and evaluate biomarkers that can be used to estimate and/or predict
both pesticide exposure and the health impacts that may result from
pesticide exposure. Successful proposals will be those that
propose research to develop markers applicable to the assessment
of pesticide exposure and/or toxicity in children. Successful
proposals will also address as many of the following factors as
possible:

Each proposal submitted in response to this solicitation should
include studies to evaluate the effectiveness of the proposed biomarker
in quantifying the event or condition of interest. To evaluate
the use of a biologic measurement as a biomarker, it is necessary
to understand the relationship between the marker and the event
or condition of interest. Determining the specificity and
sensitivity are critical components of the evaluation process.
Specificity refers to the ability of a measurement to effectively
identify negative responses in order to minimize the number of false
positives. Sensitivity refers to the ability of a measurement
to detect positive responses. One of the purposes of biomarkers
in environmental health research is to identify highly exposed individuals
or groups, so that risk can be predicted and disease prevented.
Therefore, biomarkers must not only be evaluated in terms of their
ability to assess the presence or absence of an exposure or disease,
but also on their ability to quantify the exposure, dose, or level
of disease.

The evaluation of biomarkers includes the "backward" process of
associating a biomarker with exposure, and the "forward" process
of linking a biomarker with effect. Appropriate validation
for a biomarker depends on its anticipated use. A biomarker
observed well before the onset of disease may have a low predictive
value as a biomarker of effect, but be very useful as a biomarker
of exposure, enabling long-term surveillance of an exposed population.
In contrast, a biomarker of effect that is expressed long after
exposure could be of relatively little use in exposure assessment,
but be very useful in predicting progression of disease or in calculating
risk. Animal models are useful for understanding the mechanistic
bases of the expression of markers and relationships between exposure,
early effects, and disease. The validity of a specific biomarker
of effect depends on the reliability of studies that provide the
background data, particularly on mechanisms. Estimates of
the sensitivity of a biomarker should include its evaluation in
an unexposed population or unexposed animals to determine a baseline
value for the marker. This evaluation may be difficult in
the pediatric population because of ethical issues involving invasive
procedures with little benefit to the pediatric participant.
Of particular interest are studies that incorporate pharmacokinetics.
Pediatric pharmacokinetics are an understudied area of science and
this lack of information limits the application of many known biomarkers.

References

1. National Science and Technology Council. Investing
in Our Future: a National Initiative for Americas's Children for
the 21st Century. Executive Office of the President, Washington,
DC (1997).

Approximately $5-6M will be available to support this effort.
The awards are expected to range from $150,000 to $250,000 per year
for up to three years. Awards made through this competition
are subject to the availability of funds.

Eligibility

Academic and not-for-profit institutions located in the U.S., and
state or local governments, are eligible under all existing authorizations.
Profit-making firms are not eligible to receive grants from EPA
under this program. Federal agencies and national laboratories
funded by federal agencies (Federally-funded Research and Development
Centers, FFRDCs) may not apply.

Federal employees are not eligible to serve in a principal leadership
role on a grant. FFRDC employees may cooperate or collaborate
with eligible applicants within the limits imposed by applicable
legislation and regulations. They may participate in planning,
conducting, and analyzing the research directed by the principal
investigator, but may not direct projects on behalf of the applicant
organization or principal investigator. The principal investigator's
institution may provide funds through its grant from EPA to a FFRDC
for research personnel, supplies, equipment, and other expenses
directly related to the research. However, salaries for permanent
FFRDC employees may not be provided through this mechanism.

Federal employees may not receive salaries or in other ways augment
their agency's appropriations through grants made by this program.
However, federal employees may interact with grantees so long as
their involvement is not essential to achieving the basic goals
of the grant.1 The principal investigator's
institution may also enter into an agreement with a federal agency
to purchase or utilize unique supplies or services unavailable in
the private sector. Examples are purchase of satellite data,
census data tapes, chemical reference standards, analyses, or use
of instrumentation or other facilities not available elsewhere,
etc. A written justification for federal involvement must
be included in the application, along with an assurance from the
federal agency involved which commits it to supply the specified
service.

1EPA encourages interaction between
its own laboratory scientists and grant principal investigators
for the sole purpose of exchanging information in research areas
of common interest that may add value to their respective research
activities. However, this interaction must be incidental to
achieving the goals of the research under a grant. Interaction
that is "incidental" is not reflected in a research proposal and
involves no resource commitments.

Potential applicants who are uncertain of their eligibility should
contact Dr. Robert E. Menzer in NCER, phone (202) 564-6849, email:
menzer.robert@epa.gov.

Standard
Instructions for Submitting an Application

A set of special instructions on how applicants should apply for
an NCER grant is found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/,
Standard Instructions for Submitting a STAR Application. The
necessary forms for submitting an application will be found on this
web site.

Sorting Codes

The need for a sorting code to be used in the application and for
mailing is described in the Standard Instructions for Submitting
a STAR Application. The sorting code for applications submitted
in response to this solicitation is 2000-STAR-D1. The
deadline for receipt of the application by NCER is no later than
4:00 p.m. ET, March 9, 2000.

Contacts

Further information, if needed, may be obtained from the EPA official
indicated below. E-mail inquiries are preferred.